Drug resistance in chemotherapy treatment

One obstacle to success with chemotherapy treatment is drug resistance. Patients receiving chemotherapy can develop resistance to previously effective drugs to the point that the drugs are no longer effective. Resistance – also called tachyphylaxis – occurs when a cancer cell develops the ability to keep the chemotherapy drug from entering it, or reduces the amount that can enter to a level that does not cause damage. Tolerance and desensitization are terms also used to describe growing resistance to drugs. (Tachyphylaxis is more precisely quickly acquired resistance while desensitization implies a slower process.) The cancer is said to be refractory when there is no response to a drug that normally works for that cancer.’

Sometimes a difference is made between primary resistance, which is when the cancer cells have resistance to the medicine before they encounter it, and acquired resistance, which is when the tumor develops a resistance in the face of the chemotherapy drug. For acquired resistance to develop, the tumor essentially evolves.

Mechanisms

Many mechanisms cause or contribute to the development of resistance at a biochemical level. These include cell death inhibition, efflux, inactivation of the drug through chemistry, alteration of the drug targets., and the transition of the cells to mesenchymal stem cells, which is a process involved in the start of cancer metastasis.

One biochemical mechanism for resistance is when cancer cells emit a substance called p-glycoprotein, which can remove the chemotherapy drug from the cancer cell. This process self-adjusts over time, with the cancer cells emitting more p-glycoprotein in each exposure to the chemotherapy agent. The point in treatment at which resistance occurs depends largely on the type of cancer being treated, and can be at any time from the initiation of the regimen.

In the 1970s scientists developed the Goldie–Coldman hypothesis, which postulated that every solid tumor was to some extent heterogenous (had different phenotype cells), that there was always a chance that some of the mutant cells could survive a chemotherapy medicine, and that the bigger the tumor was the greater the fraction of cells were resistant.

Small-scale evolution inside the tumor

Another dynamic – or perhaps a different way of looking at the mechanics of resistance – comes from the heterogeneity of the tumor. Not all cells in the tumor are the same or react the same in the face of a chemotherapy. Even if we assume the cancer started from a single cell and grew clonally, mutations that occur lead to the creation of malignant cells that resist a given chemotherapy drug The Goldie–Coldman model of tumors assumes cells mutate and develop resistance at a rate proportional to “their intrinsic genetic instability.” This is another rationale for giving chemotherapy in combination regimens.

Chemotherapy drugs target characteristics that are different in malignant cells from healthy cells but even so, healthy cells are affected by the drugs. A big enough dose of the chemo agent would eliminate the cancer cells, but would kill so many healthy cells the patient might die. The therapeutic window is narrow. To cope with this problem, doctors administer chemotherapy (and radiation treatment) in cycles – repeated administration at smaller doses so the drug doesn’t kill the patient.

Unfortunately this approach does not kill all of the cancer cells. Sometimes it works as an effective therapy, but sometimes malignant cells survive and give rise to a newly hardened tumor.

Fibroblasts that are not malignant are induced by the chemotherapy to secrete Wnt16B. This is a protein that is taken up by the malignant cells and makes them hardier. What this means is that even non-malignant cells work to protect the tumor in the face of an assault by chemotherapy. If a patient receives drugs in a dose-dense cycle, it might lead to more resistant tumors in the future.

Drug designers need to worry about not just the cancerous cells but also the surrounding cells and microenvironment inside the tumor. Indeed, scientists are now looking into ways to block Wnt signaling.

Sanctuary Sites

If metastasizing cells get to certain parts of the body, they are more likely to survive cancer treatment, including chemotherapy. These areas are called sanctuary sites, and the brain and testes are common sites where cancer survives.

Born that way or made?

Are tumors naturally resistant to chemo medications, or do they acquire resistance during the course of the treatment? Both. The principles of evolution apply to cells in a tumor just as they apply to individuals. A chemotherapy treatment may kill some fraction of malignant cells. That fraction may be high, but it is not 100 percent. Some cancer cells remain even if the patient no longer has cancer in a clinical sense – the remaining tumor may be so small it cannot be detected. In some cases the patient’s immune system is able to control what’s left, and the patient can live for decades with the cancer in remission. In other cases, the remnant of malignant cells roars back as a cancer that is resistant to the chemotherapy employed.

Let’s say 0.5 percent of cells had a natural resistance and the initial chemo regimen destroyed 99 percent of the malignant cells. After that regimen, 50 percent of the remaining cells have resistance. When the tumor grows back, half of the cells now cannot be affected with chemo. Another round of medicine now kills only half of the tumor cells, and when the tumor grows back, it is now resistant to the chemotherapy agent. Medicine has therefore forced the evolution of the malignant cells within the tumor.

Progress in overcoming resistance?

Working with one form of lung cancer, Israeli researcher Yosef Yarden found how malignancies develop resistance. This lung cancer responded to initial chemotherapy treatment and appeared to go into complete remission before reappearing in patients months later. The second coming of the cancer resisted chemotherapy. Yarden’s researchers found the cancer “rewired a main internal communications line” and produced new receptors that responded to growth signals but not to the chemotherapy agent. It’s almost like the cancer is clever and has a mind of its own.

Chemotherapy drugs that are most often associated with resistance include paclitaxel, docetaxel, vinorelbine, vincristine, vinblastine, doxorubicin, daunorubicin, epirubicin, etoposide, teniposide, topotecan, dactinomycin, and mitomycin C. These drugs are used to treat a wide variety of cancers – solid tumors to lymphoma. These drugs also come from several different families of chemotherapy drugs, so the phenomenon of drug resistance is not confined to one family of cancer drugs or one type of cancer.

In order to combat resistance, chemotherapy drugs are often given in combination in the hopes that the cancer will fail to resist at least one of the drugs in the combination. Once a cancer has developed resistance to one type of drug, it is more likely to develop resistance to other drugs, making treatment more difficult. This is why it is important to determine the best possible drug combination and to use it first when the probability of resistance is lowest. Another interesting method of emerging interest – though it is not yet used widely – is administering the chemotherapy drug on a long regimen of low doses.

Research is ongoing as scientists try to find a way to combat resistance. European researchers are studying the action of an enzyme called TAK-1 as it relates to extreme resistance found in pancreatic cancer. A substance was developed that inhibits the TAK-1 enzyme, and when this substance was given to mice along with the usual resistance-prone drugs, significant tumor reduction was observed. Other research is focusing on a substance called tariquidar, which attaches itself to the p-glycoprotein, hindering its ability to remove chemotherapy drugs from the cancer cell.

Resistance is one reason for remission in cancer cases.

Chemotherapy Agents

Today’s arsenal of chemotherapy agents includes many different classes of medicines. Researchers continue to find and test new drugs.